Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors

Purpose: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. Patients and Methods: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 680 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine wets reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). Results: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m2 for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. Conclusion: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2). J Clin Oncol 18:1748-1757. (C) 2000 by American Society of Clinical Oncology.